Glucose conjugates of triptolide, analogs and uses thereof

ABSTRACT

Provided are compounds generated by conjugation of triptolide with glucose to form glucose-triptolide conjugates, provides compounds with effective anti-proliferative activity and improved tolerability as compared to naturally occurring triptolide compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 35 USC § 371 National Stage application ofInternational Application No. PCT/US2017/016527 filed Feb. 3, 2017, nowpending; which claims the benefit under 35 USC § 119(e) to U.S.Application Ser. No. 62/291,416 filed Feb. 4, 2016. The disclosure ofeach of the prior applications is considered part of and is incorporatedby reference in the disclosure of this application.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates generally to anti-cancer compounds and morespecifically to glucose conjugates of triptolide and analogs thereof,and methods of treating cancer using such compounds.

Background Information

Triptolide is an active component from the traditional Chinese medicinalplant Thunder God Vine. It has been shown to possess anti-inflammatory,immunosuppressive and anticancer activities, among others. Its moleculartarget has been identified as the XPB (ERCC3) subunit of the generaltranscription factor TFIIH. It works by blocking RNAPII transcriptioninitiation and nucleoside excision repair. Triptolide and analogs havebeen developed as new anticancer and immunosuppressive drugs.Unfortunately, dose-limiting toxicity and insolubility have been majorhurdles for its development as a new drug.

SUMMARY OF THE INVENTION

The present invention is based on the seminal discovery that conjugationof triptolide with glucose to form glucose-triptolide conjugatesprovides compounds with effective anti-proliferative activity andimproved tolerability as compared to naturally occurring triptolidecompounds.

In one embodiment, the invention provides a method of treating cancer ina subject comprising administering to the subject an anti-proliferativeeffective amount of a glucose-triptolide conjugate compound, therebytreating the cancer.

The glucose-triptolide conjugate compounds have the structure of FormulaI:T&A-L₁-Sugar   (I)

wherein the T&A moiety is triptolide or one of its analogs, and can beselected from compounds 1 to 18:

wherein L₁ can be selected from —X—Y—Z—, wherein X and Z canindividually and independently be a direct bond, —CH₂—, —C(O)—, —SO—,—SO₂—, —OPO—, —OPO₂—, and wherein Y is a direct bond, a substituted orunsubstituted —(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)O(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)C(O)O(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)NH(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)C(O)NH(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted—(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)O(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)O(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)NH(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)NH(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted—(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)O(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)O(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)NH(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)NH(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)S(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkynyl-, wherein each alkyl, alkenyl andalkynyl group may be optionally substituted with alkyl, alkoxy, amino,hydroxyl, oxo, aryl, heteroaryl, carboxyl, cyano, nitro, ortrifluoromethyl;

wherein the sugar can be selected from compounds 19 to 53:

The cancer may be one of the following, but not limited to bladdercancer, breast cancer, ovarian cancer, pancreatic cancer, and gastriccancer, cervical cancer, colon cancer, endometrial cancer, head and neckcancer, lung cancer, melanoma, multiple myeloma, leukemia, non-hodgkin'slymphoma, prostate cancer, rectal cancer, malignant melanomas,alimentary/gastrointestinal tract cancer, liver cancer, skin cancer,lymphoma, kidney cancer, muscle cancer, bone cancer, brain cancer, eyeor ocular cancer, rectal cancer, colon cancer, cervical cancer, bladdercancer, oral cancer, benign and malignant tumors, stomach cancer, corpusuteri, testicular cancer, renal cancer, throat cancer, acute lymphocyticleukemia, acute myelogenous leukemia, Ewing's Sarcoma, Kaposi's Sarcoma,basal cell carcinoma and squamous cell carcinoma, small cell lungcancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma,hemangioendothelioma, Wilms Tumor, neuroblastoma, mouth/pharynx cancer,esophageal cancer, larynx cancer, neurofibromatosis, tuberous sclerosis,hemangiomas, and lymphangiogenesis.

In another embodiment, the cancer is prostate cancer.

In another embodiment, the cancer is metastatic cancer.

In another embodiment, T&A moiety is compound 1 and the sugar iscompound 19, 20, 37 or 38.

In another embodiment, L₁ is a direct bond, —COCH₂CH₂CO—, or —CH₂—.

In another embodiment, T&A moiety is compound 1 and the sugar iscompound 19.

In another embodiment, the glucose triptolide conjugate compound has aFormula G1-9. In a preferred embodiment the compound is Formula G4.Formula G1-9 are illustrated in the structures provided herein. Theinvention also provides a pharmaceutical composition comprising thecompounds listed above.

The method of treatment includes administration intravenously, such asat a dosage of about 0.1 mg/kg to 2 mg/kg per dosage. In one aspect, thecompound is administered once daily for up to about 4 weeks. The methodmay further include administering a chemotherapeutic compound, forexample, prior to, simultaneously with, or following administration of acompound of the invention.

In another embodiment, the method of synthesizing a glucose-triptolideconjugate compound includes synthetic scheme I, II or III. These schemesare provided herein.

In another embodiment, an anti-proliferative effective amount of aglucose-triptolide conjugate compound is administered to a subject in amethod to treat possible organ rejection in subjects that have undergonean organ transplant.

In another embodiment, an anti-proliferative effective amount of aglucose-triptolide conjugate compound is administered to a subject in amethod to treat autoimmune diseases.

Examples of immune related diseases that can be treated include but arenot limited to: Acute disseminated encephalomyelitis (ADEM), Addison'sdisease, Ankylosing spondylitis, Antiphospholipid antibody syndrome,Autoimmune hemolytic anemia, Autoimmune hepatitis, Autoimmune inner eardisease, Autoimmune Lymphoproliferative Syndrome (ALPS), Autoimmunepolyendocrine/polyglandular syndrome, Autoimmune thrombocytoipeniapurpura, Balo disease, Behçet disease, Bullous pemphigoid,Cardiomyopathy, Celiac sprue-dermatitis herpetiformis, Chronic fatigueimmune dysfunction syndrome (CFIDS), Chronic inflammatory demyelinatingneuropathy, Cicatrical pemphigoid, Coeliac disease, Cold agglutinindisease, CREST syndrome, Crohn's disease, Cystic fibrosis, Degosdisease, Dermatomyositis, Diabetes (Type I or Juvenile onset), Earlyonset dementia, Eczema, Endotoxin shock, Essential mixedcryoglobulinemia, Familial Mediterranean fever, Fibromyalgia,Fibromyositis, Goodpasture's syndrome, Graves' disease, Guillain-Barrêsyndrome (GBS), Hashimoto's thyroidosis, Hidradenitis suppurativa,Idiopathic pulmonary fibrosis, Idiopathic thrombocytopenic purpura, IgAnephropathy, Lambert-Eaton Myasthenic Syndrome, Leukemia, Lichen planus,Ménière disease, Mixed connective tissue disease, Multiple sclerosis,Multiphasic disseminated encephalomyelitis, Myasthenia gravis,Neuromyelitis Optica, Paraneoplastic Syndromes, Pemphigus, Pemphigusvulgaris, Pernicious anemia, Polyarteritis nodosum, Polychondritis,Polymyalgia rhematica, Polymyositis, Primary agammaglobulinemia, Primarybiliary cirrhosis, Plaque Psoriasis, Psoriatic arthritis, Raynaudphenomenon, Reiter syndrome, Restenosis following angioplasty, Rheumaticfever, Rheumatoid arthritis, Rheumatoid psoriasis, Sarcoidosis,Scleroderma, Sepsis, Sezary's disease, Sjögren's syndrome, Stiff-personsyndrome, Lupus including Systemic lupus erythematosis (SLE), Takayasuarteritis, Temporal arteritis (also known as “giant cell arteritis”),Transplant or Allograft rejection, Ulcerative colitis, Uveitis,Vasculitis, Vitiligo, Graft vs Host disease, pustular psoriasis, andWegener's granulomatosis (now termed Granulomatosis with Polyangiitis(GPA), inflammatory bowel disease, Acute necrotizing hemorrhagicleukoencephalitis, Agammaglobulinemia, Alopecia areata, Amyloidosis,Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmuneangioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia,Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune innerear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis,Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thyroiddisease, Autoimmune urticarial, Axonal & neuronal neuropathies,Castleman disease, Celiac disease, Chagas disease, Chronic fatiguesyndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP),Chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strausssyndrome, Cicatricial pemphigoid/benign mucosal pemphigoid, Coganssyndrome, Congenital heart block, Coxsackie myocarditis, CREST disease,Demyelinating neuropathies, Dermatitis herpetiformis, Devic's disease(neuromyelitis optica), Discoid lupus, Dressler's syndrome,Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis,Erythema nodosum, Experimental allergic encephalomyelitis, Evanssyndrome, Fibrosing alveolitis, Giant cell arteritis (temporalarteritis), Giant cell myocarditis, Glomerulonephritis, Granulomatosiswith Polyangiitis (GPA) (formerly called Wegener's Granulomatosis),Hashimoto's encephalitis, Hashimoto's thyroiditis, Hemolytic anemia,Henoch-Schonlein purpura, Herpes gestationis, Hypogammaglobulinemia,Idiopathic thrombocytopenic purpura (ITP), IgG4-related sclerosingdisease, Immunoregulatory lipoproteins, Inclusion body myositis,Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (Type 1diabetes), Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome,Leukocytoclastic vasculitis, Lichen sclerosus, Ligneous conjunctivitis,Linear IgA disease (LAD), Lupus (SLE), Lyme disease, chronic,Microscopic polyangiitis, Mooren's ulcer, Mucha-Habermann disease,Myositis, Narcolepsy, Neutropenia, Ocular cicatricial pemphigoid, Opticneuritis, Palindromic rheumatism, PANDAS (Pediatric AutoimmuneNeuropsychiatric Disorders Associated with Streptococcus),Paraneoplastic cerebellar degeneration, Paroxysmal nocturnalhemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turnersyndrome, Pars planitis (peripheral uveitis), Pemphigus, Peripheralneuropathy, Perivenous encephalomyelitis, POEMS syndrome, Type I, II, &III autoimmune polyglandular syndromes, Postmyocardial infarctionsyndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primarybiliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriaticarthritis, Idiopathic pulmonary fibrosis, Pyoderma gangrenosum, Pure redcell aplasia, Reactive Arthritis, Reflex sympathetic dystrophy,Relapsing polychondritis, Restless legs syndrome, Retroperitonealfibrosis, Rheumatic fever, Schmidt syndrome, Scleritis, Sperm &testicular autoimmunity, Subacute bacterial endocarditis (SBE), Susac'ssyndrome, Sympathetic ophthalmia, Thrombocytopenic purpura (TTP),Tolosa-Hunt syndrome, Transverse myelitis, Type 1 diabetes,Undifferentiated connective tissue disease (UCTD) and Vesiculobullousdermatosis.

In another embodiment, a library of glucose conjugates of triptolide andanalogs thereof, is used to screen for compounds for treating cancer.

In another embodiment, a library of glucose conjugates of triptolide andanalogs thereof, is used to screen for compounds for treating possibleorgan rejection.

In another embodiment, a library of glucose conjugates of triptolide andanalogs thereof, is used to screen for compounds for treating autoimmunedisease.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1B. (a) The structure of triptolide and glucose conjugatedanalogs. (b) The octanol-water partition coefficient log P of differentanalogs using Interactive log P calculator.

FIGS. 2A-2D. (a) Effects of G1-5 on HeLa cell proliferation. (b) Effectsof G1-5 on ATPase activity of TFIIH in vitro. (c) Effects of G3 and G4on the stability of RNAPII catalytic subunit. (d) Effects of G1, G2 andG5 on the stability of the RNAPII catalytic subunit.

FIG. 3. Effects of triptolide and glucose-triptolide conjugate G4 in ametastatic mouse prostate cancer model. The injected prostate cancercells expressed luciferase, which was detected by imaging of liveanimals.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on trying to solve the issues ofsolubility and toxicity associated with triptolide. It was hypothesizedthat if triptolide could be conjugated to glucose, the twoaforementioned problems associated with triptolide could be addressed.The glucose-triptolide conjugates would be preferentially taken up bycancer cells and they should also exhibit much higher water solubilitydue to the water solubility of glucose moiety.

As used herein, the term “cancer” or “cancerous growth” means theuncontrolled, abnormal growth of cells and includes within its scope allthe well-known diseases that are caused by the uncontrolled and abnormalgrowth of cells. Non-limiting examples of common cancers include bladdercancer, breast cancer, ovarian cancer, pancreatic cancer, and gastriccancer, cervical cancer, colon cancer, endometrial cancer, head and neckcancer, lung cancer, melanoma, multiple myeloma, leukemia (e.g. myeloid,lymphocytic, myelocytic and lymphoblastic leukemias), non-hodgkin'slymphoma, prostate cancer, rectal cancer, and malignant melanomas.

In addition to invention compounds, one of skill in the art wouldrecognize that chemotherapeutic agents can be used prior to,simultaneously with or following treatment with invention compounds.Illustrative agents include but are not limited to, taxol, cytochalasinB, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide,tenoposide, vincristine, vinblastine, colchicin, doxorubicin,daunorubicin, dihydroxy anthracin dione, mitoxantrone, mithramycin,actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine,tetracaine, lidocaine, propranolol, and puromycin and analogs orhomologs thereof. Therapeutic antibodies or other proteins are alsoenvisioned in combination therapies of the invention.

The following examples are intended to illustrate but not limit theinvention.

Example 1

Synthesis of Glucose-Triptolide Conjugates

This example illustrates the synthesis of glucose-conjugated triptolidecompounds. Five glucose conjugates with different types of linkersconnecting glucose to triptolide were synthesized, designated G1-G5(schemes I-III). Based on calculation, the Octanol-water partitioncoefficient, Log P, values were significantly improved over triptolideitself (FIG. 1).

The activity of the different glucose-triptolide conjugates was assessedin vitro (FIG. 2). It was found that they differ in theiranti-proliferative activity as measured by tritiated thymidineincorporation with G4 and G3 showing moderate activity, while G1, G2 andG5 exhibiting significantly reduced activity. The ability of the glucoseconjugates to inhibit the ATPase activity of XPB in the TFIIH complexwas also addressed. Interestingly, none of the five glucose conjugatesshowed appreciable inhibitory activity, suggesting that the cellularactivity was a result of breakdown of the conjugates either in cellculture or upon entry into cells. Lastly, the ability of the glucoseconjugates to cause degradation of the catalytic subunit of RNAPII wasdetermined, an effect that has been previously observed for triptolide.In parallel with the antiproliferative activity, G4 was most active ininducing RNAPII catalytic subunit degradation with G3 showing weakeractivity and the rest of the glucose conjugates showing little activity.

Example 2

In Vivo Activity of Glucose-Triptolide Conjugates

The in vivo antitumor activity of the glucose-triptolide conjugate G4was determined using an established metastatic prostate cancer model(Reference 1). In this model, the luciferase-expressing prostate cancerline PC3/ML was injected into NOD/SCID/IL2rγ^(null) (NSG) mice throughthe tail vein. The metastasis of the injected prostate cancer cells intoliver, kidney, lung and bone can be monitored in live animals bybioluminescent imaging (BLI). It was shown that this is a reliable modelwith reproducible liver metastasis and all animals succumb by Week 7after injection of cells (or Week 4 after initiation of treatments). Inpreliminary experiments, it was found that the tolerable treatment doseof triptolide to be 0.2 mg/kg and that of G4 to be 1 mg/kg. Three weeksafter cell injection, each compound was given once daily by IP at thosedoses for a total of 4 weeks. The surviving animals were continuouslymonitored upon termination of compound administration. As shown in FIG.3, mice treated with 11 had lower tumor burden during Weeks 1 and 2compared with those treated with triptolide. At the end of Week 4, bothtreatment groups showed undetectable tumor cells while all animals inthe untreated groups died. Upon termination of compound administration,tumors immediately returned in animals treated with triptolide. But notumor cells were detectable in those treated with G4 till the end of theexperiment, revealing sustained anticancer activity of G4 in vivo.

Example 3

Other glucose triptolide conjugates with structures similar to FormulasG1-G5 are included in the present invention. Such structures arerepresented by Formulas G6-G9, wherein R is a direct bond, substitutedor unsubstituted —(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)O(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)C(O)—,substituted or unsubstituted —(CH₂)_(n)C(O)(C₁-C₆)alkyl-, substituted orunsubstituted —(CH₂)_(n)C(O)O(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)NH(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)C(O)NH(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted—(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)O(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)O(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)NH(C₁-C₆)alkenyl-, substituted or unsubstituted—(C₂)_(n)C(O)NH(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted—(C₂—C)alkynyl-, substituted or unsubstituted—(CH₂)_(n)O(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)O(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)NH(C₁-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)NH(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)S(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkynyl-, wherein each alkyl, alkenyl andalkynyl group may be optionally substituted with alkyl, alkoxy, amino,carboxyl, cyano, nitro, or trifluoromethyl, wherein each n isindependently an integer selected from 0, 1, 2, 3, 4, 5, and 6.

Example 4

Other glucose triptolide conjugates that are included in the presentinvention are compounds of Formula I:T&A-L₁-Sugar   (I)wherein the T&A moiety is triptolide or one of its analogs, and can beselected from compounds 1 to 18:

wherein L₁ can be selected from —X—Y—Z—, wherein X and Z canindividually and independently be a direct bond, —CH₂—, —C(O)—, —SO—,—SO₂—, —OPO—, —OPO₂—; Y is a direct bond, a substituted or unsubstituted—(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)O(C₁-C₆)alkyl-,substituted or unsubstituted —(CH₂)_(n)C(O)—, substituted orunsubstituted —(CH₂)_(n)C(O)(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)C(O)O(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)NH(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)C(O)NH(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted—(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)O(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)O(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)(O)NH(C₁-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)NH(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted—(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)O(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)O(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)NH(C₁-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)NH(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)S(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkynyl-, wherein each alkyl, alkenyl andalkynyl group may be optionally substituted with alkyl, alkoxy, amino,hydroxyl, oxo, aryl, heteroaryl, carboxyl, cyano, nitro, ortrifluoromethyl;

wherein the sugar can be selected from compounds 19 to 53:

Although the invention has been described with reference to the aboveexample, it will be understood that modifications and variations areencompassed within the spirit and scope of the invention. Accordingly,the invention is limited only by the following claims.

REFERENCES

The following reference is relied upon and incorporated herein in itsentirety.

-   1. Bhatnagar A, Wang Y, Mease R C, Gabrielson M, Sysa P, Minn I,    Green G, Simmons B, Gabrielson K, Sarkar S, Fisher P B, Pomper M G.    AEG-1 promoter-mediated imaging of prostate cancer. Cancer Res.    2014; 74(20):5772-81.

What is claimed is:
 1. A compound of Formula I:T&A-L₁-Sugar   (I) wherein the T&A moiety is triptolide or one of itsanalogs, and can be selected from compounds 1 to 18:

wherein L₁ can be selected from —X—Y—Z—, wherein X and Z canindividually and independently be a direct bond, —CH₂—, —C(O)—, —SO—,—SO₂—, —OPO—, —OPO₂—, and wherein Y is a substituted or unsubstituted—(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)O(C₁-C₆)alkyl-,substituted or unsubstituted —(CH₂)_(n)C(O)(C₁-C₆)alkyl-, substituted orunsubstituted —(CH₂)_(n)C(O)O(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)NH(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)C(O)NH(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted—(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)O(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)O(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)NH(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)NH(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted—(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)O(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)O(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)NH(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)NH(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)S(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkynyl-, wherein each alkyl, alkenyl andalkynyl group may be optionally substituted with alkyl, alkoxy, amino,hydroxyl, oxo, aryl, heteroaryl, carboxyl, cyano, nitro, ortrifluoromethyl; wherein n is an integer independently selected from 0,1, 2, 3 4, 5, and 6; wherein the sugar can be selected from compounds 19to 30, 33 to 48, and 51 to 53:


2. The compound of Formula I of claim 1, wherein T&A moiety is compound1 and the sugar is compound 19, 20, 37 or
 38. 3. The compound of claim2, wherein L₁ is—COCH₂CH₂CO— or —CH₂—.
 4. The compound of claim 3,wherein T&A is compound 1, L₁ is —COCH₂CH₂CO— and the sugar is compound19.
 5. A method of treating cancer in a subject comprising administeringto the subject an anti-proliferative effective amount of a compound ofFormula 1:T&A-L₁-Sugar   (I) wherein the T&A moiety is triptolide or one of itsanalogs, and can be selected from compounds 1 to 18:

wherein L₁ can be selected from —X—Y—Z—, wherein X and Z canindividually and independently be a direct bond, —CH₂—, —C(O)—, —SO—,—SO₂—, —OPO—, —OPO₂—, and wherein Y is a substituted or unsubstituted—(C₁-C₆)alkyl-, substituted or unsubstituted —(CH₂)_(n)O(C₁-C₆)alkyl-,substituted or unsubstituted —(CH₂)_(n)C(O)(C₁-C₆)alkyl-, substituted orunsubstituted —(CH₂)_(n)C(O)O(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)NH(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)C(O)NH(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(CH₂)_(n)S(C₁-C₆)alkyl-, substituted or unsubstituted—(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)O(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)O(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)NH(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)NH(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkenyl-, substituted or unsubstituted—(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)O(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)O(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)NH(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)NH(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)S(C₂-C₆)alkynyl-, substituted or unsubstituted—(CH₂)_(n)C(O)(CH₂)_(n)S(C₂-C₆)alkynyl-, wherein each alkyl, alkenyl andalkynyl group may be optionally substituted with alkyl, alkoxy, amino,hydroxyl, oxo, aryl, heteroaryl, carboxyl, cyano, nitro, ortrifluoromethyl; wherein n is an integer independently selected from 0,1, 2, 3 4, 5, and 6; wherein the sugar can be selected from compounds 19to 30, 33 to 48, and 51 to 53:

hereby treating the cancer.
 6. The method of claim 5, wherein thecompound is a compound of claim
 2. 7. The method of claim 5, wherein thecompound is a compound of claim
 3. 8. The method of claim 5, wherein thecompound is a compound of claim
 4. 9. The method of claim 5, wherein thecancer is selected from the group consisting of bladder cancer, breastcancer, ovarian cancer, pancreatic cancer, and gastric cancer, cervicalcancer, colon cancer, endometrial cancer, head and neck cancer, lungcancer, melanoma, multiple myeloma, leukemia, non-hodgkin's lymphoma,prostate cancer, rectal cancer, malignant melanomas,alimentary/gastrointestinal tract cancer, liver cancer, skin cancer,lymphoma, kidney cancer, muscle cancer, bone cancer, brain cancer, eyeor ocular cancer, rectal cancer, colon cancer, cervical cancer, bladdercancer, oral cancer, benign and malignant tumors, stomach cancer, corpusuteri, testicular cancer, renal cancer, throat cancer, acute lymphocyticleukemia, acute myelogenous leukemia, Ewing's Sarcoma, Kaposi's Sarcoma,basal cell carinoma and squamous cell carcinoma, small cell lung cancer,choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma,Wilms Tumor, neuroblastoma, mouth/pharynx cancer, esophageal cancer,larynx cancer, neurofibromatosis, tuberous sclerosis, hemangiomas, andlymphangiogenesis.
 10. The method of claim 9, wherein the cancer isprostate cancer.
 11. The method of claim 9, wherein the cancer ismetastatic cancer.
 12. The method of claim 9, wherein the compound isadministered intravenously.
 13. The method of claim 12, furthercomprising administering a chemotherapeutic compound.
 14. Apharmaceutical composition comprising a compound of claim
 3. 15. Amethod of treating possible organ rejection in a subject receiving anorgan transplant comprising administering to the subject ananti-proliferative effective amount of a glucose-triptolide conjugatecompound, thereby treating the possible organ rejection.
 16. The methodof claim 15, wherein the compound is a compound of claim
 1. 17. Themethod of claim 15, wherein the compound is a compound of claim
 2. 18.The method of claim 15, wherein the compound is a compound of claim 3.19. The method of claim 15, wherein the compound is a compound of claim4.
 20. The method of claim 15, wherein the compound is administeredintravenously.
 21. A method of treating an autoimmune disease in asubject comprising administering to the subject an anti-proliferativeeffective amount of a glucose-triptolide conjugate compound, therebytreating the autoimmune disease.
 22. The method of claim 21, wherein thecompound is a compound of claim
 1. 23. The method of claim 21, whereinthe compound is a compound of claim
 2. 24. The method of claim 21,wherein the compound is a compound of claim
 3. 25. The method of claim21, wherein the compound is a compound of claim
 4. 26. The method ofclaim 21, wherein the autoimmune disease is selected from the groupconsisting of Acute disseminated encephalomyelitis (ADEM), Addison'sdisease, Ankylosing spondylitis, Antiphospholipid antibody syndrome,Autoimmune hemolytic anemia, Autoimmune hepatitis, Autoimmune inner eardisease, Autoimmune Lymphoproliferative Syndrome (ALPS), Autoimmunepolyendocrine/polyglandular syndrome, Autoimmune thrombocytoipeniapurpura, Balo disease, Behçet disease, Bullous pemphigoid,Cardiomyopathy, Celiac sprue-dermatitis herpetiformis, Chronic fatigueimmune dysfunction syndrome (CFIDS), Chronic inflammatory demyelinatingneuropathy, Cicatrical pemphigoid, Coeliac disease, Cold agglutinindisease, CREST syndrome, Crohn's disease, Cystic fibrosis, Degosdisease, Dermatomyositis, Diabetes (Type I or Juvenile onset), Earlyonset dementia, Eczema, Endotoxin shock, Essential mixedcryoglobulinemia, Familial Mediterranean fever, Fibromyalgia,Fibromyositis, Goodpasture's syndrome, Graves' disease, Guillain-Barrésyndrome (GBS), Hashimoto's thyroidosis, Hidradenitis suppurativa,Idiopathic pulmonary fibrosis, Idiopathic thrombocytopenic purpura, IgAnephropathy, Lambert-Eaton Myasthenic Syndrome, Leukemia, Lichen planus,Ménière disease, Mixed connective tissue disease, Multiple sclerosis,Multiphasic disseminated encephalomyelitis, Myasthenia gravis,Neuromyelitis Optica, Paraneoplastic Syndromes, Pemphigus, Pemphigusvulgaris, Pernicious anaemia, Polyarteritis nodosum, Polychondritis,Polymyalgia rhematica, Polymyositis, Primary agammaglobulinemia, Primarybiliary cirrhosis, Plaque Psoriasis, Psoriatic arthritis, Raynaudphenomenon, Reiter syndrome, Restenosis following angioplasty, Rheumaticfever, Rheumatoid arthritis, Rheumatoid psoriasis, Sarcoidosis,Scleroderma, Sepsis, Sezary's disease, Sjögren's syndrome, Stiff-personsyndrome, Lupus including Systemic lupus erythematosis (SLE), Takayasuarteritis, Temporal arteritis (also known as “giant cell arteritis”),Transplant or Allograft rejection, Ulcerative colitis, Uveitis,Vasculitis, Vitiligo, Graft vs Host disease, pustular psoriasis, andWegener's granulomatosis (now termed Granulomatosis with Polyangiitis(GPA), inflammatory bowel disease, Acute necrotizing hemorrhagicleukoencephalitis, Agammaglobulinemia, Alopecia areata, Amyloidosis,Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmuneangioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia,Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune innerear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis,Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thyroiddisease, Autoimmune urticarial, Axonal & neuronal neuropathies,Castleman disease, Celiac disease, Chagas disease, Chronic fatiguesyndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP),Chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strausssyndrome, Cicatricial pemphigoid/benign mucosal pemphigoid, Coganssyndrome, Congenital heart block, Coxsackie myocarditis, CREST disease,Demyelinating neuropathies, Dermatitis herpetiformis, Devic's disease(neuromyelitis optica), Discoid lupus, Dressler's syndrome,Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis,Erythema nodosum, Experimental allergic encephalomyelitis, Evanssyndrome, Fibrosing alveolitis, Giant cell arteritis (temporalarteritis), Giant cell myocarditis, Glomerulonephritis, Granulomatosiswith Polyangiitis (GPA) (formerly called Wegener's Granulomatosis),Hashimoto's encephalitis, Hashimoto's thyroiditis, Hemolytic anemia,Henoch-Schonlein purpura, Herpes gestationis, Hypogammaglobulinemia,Idiopathic thrombocytopenic purpura (ITP), IgG4-related sclerosingdisease, Immunoregulatory lipoproteins, Inclusion body myositis,Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (Type 1diabetes), Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome,Leukocytoclastic vasculitis, Lichen sclerosus, Ligneous conjunctivitis,Linear IgA disease (LAD), Lupus (SLE), Lyme disease, chronic,Microscopic polyangiitis, Mooren's ulcer, Mucha-Habermann disease,Myositis, Narcolepsy, Neutropenia, Ocular cicatricial pemphigoid, Opticneuritis, Palindromic rheumatism, PANDAS (Pediatric AutoimmuneNeuropsychiatric Disorders Associated with Streptococcus),Paraneoplastic cerebellar degeneration, Paroxysmal nocturnalhemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turnersyndrome, Pars planitis (peripheral uveitis), Pemphigus, Peripheralneuropathy, Perivenous encephalomyelitis, POEMS syndrome, Type I, II, &III autoimmune polyglandular syndromes, Postmyocardial infarctionsyndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primarybiliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriaticarthritis, Idiopathic pulmonary fibrosis, Pyoderma gangrenosum, Pure redcell aplasia, Reactive Arthritis, Reflex sympathetic dystrophy,Relapsing polychondritis, Restless legs syndrome, Retroperitonealfibrosis, Rheumatic fever, Schmidt syndrome, Scleritis, Sperm &testicular autoimmunity, Subacute bacterial endocarditis (SBE), Susac'ssyndrome, Sympathetic ophthalmia, Thrombocytopenic purpura (TTP),Tolosa-Hunt syndrome, Transverse myelitis, Type 1 diabetes,Undifferentiated connective tissue disease (UCTD) and Vesiculobullousdermatosis.
 27. The method of claim 26, wherein the compound isadministered intravenously.
 28. A method of using a library of glucoseconjugates of triptolide and analogs thereof, the method comprisingscreening the glucose conjugates in the library for compounds fortreating cancer.
 29. A method of using a library of glucose conjugatesof triptolide and analogs thereof, the method comprising screening theglucose conjugates in the library for compounds for treating possibleorgan rejection.
 30. A method of using a library of glucose conjugatesof triptolide and analogs thereof, the method comprising screening theglucose conjugates in the library for compounds for treating autoimmunedisease.
 31. A method of synthesizing a compound according to claim 1with L₁ as a direct bond, the method comprising: reacting triptolidewith 2,3,4,6-tetra-O-benzyl-D-glucopyranosylortho-cyclopropylethynylbenzoate to get a glucose conjugated triptolidewith benzyl protecting groups; and obtaining a glucose conjugate oftriptolide by removing the benzyl protecting groups.
 32. A method ofsynthesizing a compound according to claim 1 with L₁ as —COCH₂CH₂CO—,the method comprising: reacting triptolide with succinic anhydride toget a modified triptolide intermediate; reacting the modified triptolideintermediate with a benzyl protected glucose to get a glucose conjugatedtriptolide with benzyl protecting groups; and obtaining a glucoseconjugate of triptolide by removing the benzyl protecting groups.
 33. Amethod of synthesizing a compound according to claim 1 with L₁ as —CH₂—,the method comprising: reacting 2,3,4,6-tetra-O-benzyl-D-glucopyranosyltrichloroacetimidate with phenylthiomethanol to get2,3,4,6-tetra-O-benzyl-D-glucopyranosyl phenylthiomethyl intermediate;reacting triptolide with the 2,3,4,6-tetra-O-benzyl-D-glucopyranosylphenylthiomethyl intermediate to get a glucose conjugated triptolidewith benzyl protecting groups; and obtaining a glucose conjugate oftriptolide by removing the benzyl protecting groups.